Medicine and Health Sciences Commons^™

2,4-Disulfonyl Phenyl Butyl Nitrone, Its Salt And Their Use As Pharmaceuticals, John M. Carney

Pharmacology and Nutritional Sciences Faculty Patents

2,4-disulfonyl α-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclosed. These materials are useful as pharmaceutical agents for oral or parenteral, e.g. intravenous administration to patients suffering from acute central nervous system oxidation as occurs in a stroke or from gradual central nervous system oxidation which can exhibit itself as progressive central nervous system function loss. The materials are also used to ameliorate the side effects of oxidative-damage causing antineoplastic disease treatments.

Phenyl Butyl Nitrone Compositions And Methods For Treatment Of Oxidative Tissue Damage, John M. Carney, Robert A. Floyd

Pharmacology and Nutritional Sciences Faculty Patents

Compositions for treating tissue damage from ischemia contain PBN, or active derivatives thereof, which are active during ischemia in preventing ATP depletion of the cells which predisposes them to subsequent injury during reperfusion, and which are active during reperfusion as oxygen radical scavengers, in a suitable pharmaceutical carrier for systemic or local administration, especially to the CNS, spinal column and eyes. Based on animal studies, the dosage for treating damage due to stroke is in the range of 10 to 300 mg/kg. Similar dosages are useful in treating damage resulting from free radical generation during inflammation, either as a product …

Optimal Survey Design For Community Intervention Evaluations: Cohort Or Cross-Sectional?, Paula Diehr

Paula Diehr

Community intervention evaluations that measure changes over time may conduct repeated cross-sectional surveys, follow a cohort of residents over time, or (often) use both designs. Each survey design has implications for precision and cost. To explore these issues, we assume that two waves of surveys are conducted, and that the goal is to estimate change in behavior for people who reside in the community at both times. Cohort designs are shown to provide more accurate estimates (in the sense of lower mean squared error) than cross-sectional estimates if (1) there is strong correlation over time in an individual's behavior at …

Gas1-Induced Growth Suppression Requires A Transactivation-Independent P53 Function., Giannino Del Sal, Elisabetta M. Ruaro, Rene Utrera, Charles N. Cole

Dartmouth Scholarship

In normal cells, induction of quiescence is accompanied by the increased expression of growth arrest-specific genes (gas). One of them, gas1, is regulated at the transcriptional level and codes for a membrane-associated protein (Gas1) which is down regulated during the G0-to-S phase transition in serum-stimulated cells. Gas1 is not expressed in growing or transformed cells, and when overexpressed in normal fibroblasts, it blocks the G0-to-S phase transition. Moreover, Gas1 blocks cell proliferation in several transformed cells with the exception of simian virus 40- or adenovirus-transformed cell lines. In this paper, we demonstrate that overexpression of Gas1 blocks cell proliferation in …

A Requirement For Bone Morphogenetic Protein-7 During Development Of The Mammalian Kidney And Eye., Andrew T. Dudley, K. M. Lyons, E. J. Robertson

Journal Articles: Genetics, Cell Biology & Anatomy

BMP-7/OP-1, a member of the transforming growth factor-beta (TGF-beta) family of secreted growth factors, is expressed during mouse embryogenesis in a pattern suggesting potential roles in a variety of inductive tissue interactions. The present study demonstrates that mice lacking BMP-7 display severe defects confined to the developing kidney and eye. Surprisingly, the early inductive tissue interactions responsible for establishing both organs appear largely unaffected. However, the absence of BMP-7 disrupts the subsequent cellular interactions required for their continued growth and development. Consequently, homozygous mutant animals exhibit renal dysplasia and anophthalmia at birth. Overall, these findings identify BMP-7 as an essential …

Survival Of Immunoglobulin G-Opsonized Toxoplasma Gondii In Nonadherent Human Monocytes., Camilo E. Fadul, Jacqueline Y. Channon, Lloyd H. Kasper

Dartmouth Scholarship

Toxoplasma gondii is a protozoan parasite that is able to penetrate human monocytes by either passive uptake during phagocytosis or active penetration. It is expected that immunoglobulin G (IgG) opsonization will target the parasite to macrophage Fc gamma receptors for phagocytic processing and subsequent degradation. Antibody-opsonized T. gondii tachyzoites were used to infect nonadherent and adherent human monocytes obtained from the peripheral blood of seronegative individuals. The infected monocytes were evaluated for the presence of intracellular parasites and the degree of parasiticidal activity. A marked difference in both the numbers of infected macrophages and numbers of parasites per 100 macrophages …

The Nascent-Polypeptide-Associated Complex: Having A "Nac" For Fidelity In Translocation., William Wickner

Dartmouth Scholarship

No abstract provided.

Survival Of Mouse Pancreatic Islet Allografts In Recipients Treated With Allogeneic Small Lymphocytes And Antibody To Cd40 Ligand., David C. Parker, Dale L. Greiner, Nancy E. Phillips, Michael C. Appel, Alan W. Steele, Fiona H. Durie, Randolph J. Noelle, John P. Mordes, Aldo A. Rossini

Dartmouth Scholarship

Combined treatment with allogeneic small lymphocytes or T-depleted small lymphocytes plus a blocking antibody to CD40 ligand (CD40L) permitted indefinite pancreatic islet allograft survival in 37 of 40 recipients that differed from islet donors at major and minor histocompatibility loci. The effect of the allogeneic small lymphocytes was donor antigen-specific. Neither treatment alone was as effective as combined treatment, although anti-CD40L by itself allowed indefinite islet allograft survival in 40% of recipients. Our interpretation is that small lymphocytes expressing donor antigens in the absence of appropriate costimulatory signals are tolerogenic for alloreactive host cells. Anti-CD40L antibody may prevent host T …

Biochemical And Molecular Characterization Of The Prostate-Specific Membrane Antigen (Psma), John Karl Troyer

Theses and Dissertations in Biomedical Sciences

Prostate cancer is the most common malignancy and the second leading cause of cancer death in males in the United States. Additionally, the number of deaths attributed to prostate cancer is increasing at a rate of approximately 8% a year. Development of new diagnostic and therapy strategies are needed in order to improve the life expectancy of patients with this disease. One tool which may allow for improvements in prostate cancer diagnosis and therapy is the monoclonal antibody (MAb) 7E11-C5.3 which was first described in 1987. Since then, the antigen recognized by MAb 7E11-C5.3 has been named the prostate specific …

Involvement Of P59FynT In Interleukin-5 Receptor Signaling, Mark W. Appleby, James D. Kerner, Sylvia Chien, Charles R. Maliszewski, Subbarao Bondada, Roger M. Perlmutter

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Previous studies implicate the nonreceptor protein tyrosine kinase (PTK) p59fyn in the propagation of signals from the B cell antigen receptor. To elucidate the functions of this kinase, we examined B cell responsiveness in mice engineered to lack the hematopoietic isoform of p59fyn. Remarkably, antigen receptor signaling was only modestly defective in fyn^Tnull B cells. In contrast, signaling from the interleukin (IL)-5 receptor which ordinarily provides a comitogenic stimulus with antiimmunoglobulin, was completely blocked. Our results document the importance of p59fyn^T in IL-5 responses in B cells, and they support a general model …

A Toxoplasma Gondii-Derived Factor(S) Stimulates Immune Downregulation: An In Vitro Model., Sakhina Haque, Azizul Haque, Lloyd H. Kasper

Dartmouth Scholarship

Suppression of the T-cell lymphoproliferative response and downregulation of interleukin 2 (IL-2) production by Toxoplasma gondii has been observed following in vivo infection. In this study, an experimental in vitro murine system was developed to evaluate the kinetics of these responses. Normal splenocytes from uninfected mice were stimulated with either concanavalin A or an anti-CD3 monoclonal antibody and cocultured with Toxoplasma tachyzoites either directly or separated by a transwell. A progressive decline in the lymphoproliferative response was observed as the concentration of parasites in culture increased. Neither heat-killed nor formaldehyde-fixed parasites stimulated this downregulatory response by the splenocytes. A decline …

Temporal Changes In The Levels Of Gamma-Aminobutyric Acid In The Brain Of The Cockroach, Leucophaea Maderae, Jonathan Newton

Masters Theses & Specialist Projects

Circadian rhythms have been shown to exist in all studied species and play an important role in their survival. The cockroach is an excellent model organism in which to study circadian systems because of the wealth of background information regarding both its anatomy and circadian system. Clock activity measured electrophysiologically in the cockroach system is 180 degrees out of phase with locomotor activity, with the maximum neural output occurring in the morning, twelve hours prior to the onset of locomotor activity. This inverse relationship of locomotor and neural activity suggests that the clock output may be inhibitory. In vertebrates, the …

Anti-Human Immunodeficiency Virus (Hiv) Activities Of Halogenated Gomisin J Derivatives, New Nonnucleoside Inhibitors Of Hiv Type 1 Reverse Transcriptase, Toshiaki Fujihashi, Hiroto Hara, Toshiya Sakata, Kazuya Mori, Hirotaka Higuchi, Akio Tanaka, Hideko Kaji, Akira Kaji

Department of Biochemistry and Molecular Biology Faculty Papers

Halogenated gomisin J (a derivative of lignan compound), represented by the bromine derivative 1506 [(6R, 7S, S-biar)-4,9-dibromo-3,10-dihydroxy-1,2,11,12-tetramethoxy-6, 7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclo-octene], was found to be a potent inhibitor of the cytopathic effects of human immunodeficiency virus type 1 (HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to 0.5 microM). Gomisin J derivatives were active in preventing p24 production from acutely HIV-1-infected H9 cells. The selective indices (toxic dose/effective dose) of these compounds were as high as > 300 in some systems. 1506 was active against 3'-azido-3'-deoxythymidine-resistant HIV-1 and acted synergistically with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reverse transcriptase (RT) in …

The Role Of Fibrinogen D Domain Intermolecular Association Sites In The Polymerization Of Fibrin And Fibrinogen Tokyo Ii (Γ275 Arg→Cys), Michael W. Mosesson, Kevin R. Siebenlist, James P. Diorio, M. Matsuda, James F. Hainfeld, J. S. Wall

Biomedical Sciences Faculty Research and Publications

Intermolecular end-to-middle domain pairing between a thrombin-exposed 'A' polymerization site in the central 'E' domain of fibrin, and a constitutive complementary 'a' site in each outer 'D' domain ('D:E'), is necessary but not alone sufficient for normal fibrin assembly, as judged from previous studies of a congenital dysfibrinogen, Tokyo II (gamma 275 arg-->cys), which showed defective fibrin clot assembly and a normal D:E interaction (Matsuda, M., M. Baba, K. Morimoto, and C. Nakamikawa, 1983. J. Clin. Invest. 72:1034-1041). In addition to the 'a' polymerization site, two other constitutive intermolecular association sites on fibrinogen D domains have been defined: between …

Asbestos Induces Nuclear Factor Kappa B (Nf-Kappa B) Dna-Binding Activity And Nf-Kappa B-Dependent Gene Expression In Tracheal Epithelial Cells., Yvonne M. Janssen, Aaron Barchowsky, Melinda Treadwell, Kevin E. Driscoll, B T. Mossman

Dartmouth Scholarship

Nuclear factor kappa B (NF-kappa B) is a transcription factor regulating expression of genes intrinsic to inflammation and cell proliferation--features of asbestos-associated diseases. In studies here, crocidolite asbestos caused protracted and dose-responsive increases in proteins binding to nuclear NF-kappa B-binding DNA elements in hamster tracheal epithelial (HTE) cells. This binding was modulated by cellular glutathione levels. Antibodies recognizing p65 and p50 protein members of the NF-kappa B family revealed these proteins in two of the DNA complexes. Transient transfection assays with a construct containing six NF-kappa B-binding DNA consensus sites linked to a luciferase reporter gene indicated that asbestos induced …

Transactivation Of The Moloney Murine Leukemia Virus And T-Cell Receptor Beta-Chain Enhancers By Cbf And Ets Requires Intact Binding Sites For Both Proteins., Wanwen Sun, Barbara J. Graves, Nancy A. Speck

Dartmouth Scholarship

The Moloney murine leukemia virus (Mo-MLV) enhancer contains binding sites (LVb and LVc) for the ets gene family of proteins and a core site that binds the polyomavirus enhancer-binding protein 2/core-binding factor (cbf) family of proteins. The LVb and core sites in the Mo-MLV enhancer contribute to its constitutive activity in T cells. All three binding sites (LVb, LVc, and core) are required for phorbol ester inducibility of the Mo-MLV enhancer. Adjacent binding sites for the ets and cbf proteins likewise constitute a phorbol ester response element within the human T-cell receptor beta-chain (TCR beta) enhancer and contribute to constitutive …

Ph And Calcium Dependence Of Hemolysis Due To Rickettsia Prowazekii: Comparison With Phospholipase Activity, David M. Ojcius, M. Thibon, C. Mounier, Alice Dautry-Varsat

All Dugoni School of Dentistry Faculty Articles

Rickettsia prowazekii invades nucleated cells through phagocytosis and subsequently proliferates in the cytoplasm of the host cell. Hemolysis and a phospholipase A2 (PLA2) activity at neutral pHs have previously been reported; even though the phagosomal environment is most likely acidic. We here show that R. prowazekii and R. typhi also lyse erythrocytes at mildly acidic pHs, compatible with an early phagosomal compartment. For R. prowazekii, hemolysis at an acidic pH but not a neutral pH is enhanced by Ca2+, raising the possibility that more than one membranolytic factor may be produced by the rickettsiae. The rickettsiae alone display PLA2 activity, …

Site Directed Mutagenesis Of A Putative Protease Cleavage Site Within The 105 Kilodation Protein Of Southern Bean Mosaic Virus, Jingyu Shi

Masters Theses & Specialist Projects

There are four open reading frames (ORF) in three positive-sense translational phases of Southern Bean Mosaic Virus (SBMV). ORF2 codes for a 105 KDa polyprotein which is proposed to be autocatalytically cleaved into smaller functional proteins. Amino acid sequence homology between the SBMV and poliovirus, foot and mouth disease virus, and cowpea mosaic virus reveal that SBMV has a similar genomic organization to picornaviruses with a conserved order: Vpg (Viral protein, genome-linked )-protease-replicase. Two Gln-Ser (QS) amino acid pairs within the 105 KDa polyprotein, C75= 930-936, C60= 1305-1310, are proposed to be the cleavage sites based on 1) similar structural …

Antibody Response To Trypanosoma Cruzi During The Course Of Infection In Mice Held At Elevated Environmental Temperature, Lianyong Gao

Masters Theses & Specialist Projects

It has been demonstrated that changes in environmental temperature can influence the resistance of mice to Trypanosoma cruzi (the causative agent of Chagas' disease in humans) infection. This increased resistance is not only reflected by decreased parasitemias and increased longevity but also by enhanced parasite-specific and nonspecific immune responsiveness in infected mice. The antibody response to heterologous antigen has been demonstrated to be greatly enhanced in infected mice held at elevated temperature. However, the parasite-specific antibody response was reported to be lower in infected mice maintained at 36°C than at room temperature (RT) during early stage of infection, although it …

Identification Of An Idiotypic Peptide Recognized By Autoantibodies In Human Immunodeficiency Virus-1-Infected Individuals, Q. L. Wang, H.-T. Wang, Edwin Blalock, Sybille Müller, Heinz Köhler

Markey Cancer Center Faculty Publications

Antibodies against HIV-1 proteins in HIV-1-infected individuals share a cross-reactive idiotype defined by the monoclonal antiidiotypic antibody 1F7 (5). Using a computer algorithm based on the molecular recognition theory, regions of inverse hydropathy between the variable sequence of 1F7 and human monoclonal anti-HIV-1 antibodies were identified, which are assumed to be involved in idiotype-antiidiotype contacts. A peptide was designed from the proposed contact in the variable heavy chain framework 3-complementarity determining region 3 (FR3-CDR3) of human antibodies and was synthesized. This peptide is recognized by the antiidiotype 1F7 and inhibits the binding of 1F7 to human anti-HIV-1 antibodies which express …

The Effect Of Dietary Supplemented Vitamin E And Selenium On Experimental Chagas' Disease, Brenda Bennett

Masters Theses & Specialist Projects

Dietary supplementation with increased levels of vitamin E can enhance the immune system of C3HeB/FeJ mice to enable many of them to survive an otherwise lethal dose of Trypanosoma cruzi, the causative agent of Chagas' disease. To study the role of diet on the course of experimental Chagas' disease, C3HeB/FeJ mice were fed pelleted, synthetic food containing no vitamin E and selenium, 800 IU/kg vitamin E, 2 ppm selenium, or food containing 800 IU/kg vitamin E plus 2 ppm selenium. Mice on synthetic food were compared to control mice fed a commonly used Purina rodent chow # 5001. After diet …

The Sea Anemone Purine, Caissarone: Adenosine Receptor Antagonism, Roland A. Cooper, Josecarlos De Freitas, Frank Porreca, Cynthia M. Eisenhour, Ronald Lukas, Ryan J. Huxtable

Roland A. Cooper

Breaking The Matches In A Paired T-Test For Community Interventions When The Number Of Pairs Is Small, Paula Diehr

Paula Diehr

There is considerable interest in community interventions for health promotion, where the community is the experimental unit. Because such interventions are expensive, the number of experimental units (communities) is usually small. Because of the small number of communities involved, investigators often match treatment and control communities on demographic variables before randomization to minimize the possibility of a bad split. Unfortunately, matching has been shown to decrease the power of the design when the number of pairs is small, unless the matching variable is very highly correlated with the outcome variable (in this case, with change in the health behaviour). We …

Immune Response To The Carcinoembryonic Antigen In Patients Treated With An Anti-Idiotype Antibody Vaccine, Kenneth A. Foon, Mala Chakraborty, William J. John, Amanda Sherratt, Heinz Köhler, Malaya Bhattacharya-Chatterjee

Markey Cancer Center Faculty Publications

We have generated an IgG1 murine monoclonal anti-idiotype antibody (Ab2) designated 3H1, which mimics a specific epitope on the carcinoembryonic antigen (CEA). Patients with CEA positive tumors are immunologically "tolerant" to CEA. We used 3H1 as a surrogate for CEA for vaccine therapy of 12 patients with advanced colorectal cancer. Each of the patients received a minimum of four intracutaneous injections of aluminum hydroxide precipitated 3H1 at either 1, 2, or 4 mg dosage per injection. 9 of 12 patients demonstrated anti-anti-idiotypic (Ab3) response to 3H1. All nine patients generated specific anti-CEA antibody demonstrated by reactivity with radiolabeled purified CEA; …

A National Minority Organ/Tissue Transplant Education Program: The First Step In The Evolution Of A National Minority Strategy And Minority Transplant Equity In The Usa, Clive O. Callender, Alvina S. Bey, Patrice V. Miles, Curtis L. Yeager

Trotter Review

In 1978, members of the Southeastern Organ Procurement Foundation approached us concerning the disparity between the large number of African American patients, 50% to 70% of all patients on dialysis (artificial kidney machines), and the small number of African American donors (3%), and asked us why and what could be done about it? From my perspective as an African American transplant surgeon at Howard University, these observations piqued my curiosity and I agreed to investigate them. Our investigation took us into three areas: 1. An evaluation of the data regarding transplantation in patients at the Howard University Hospital Transplant Center …

A Tef-1-Independent Mechanism For Activation Of The Simian Virus 40 (Sv40) Late Promoter By Mutant Sv40 Large T Antigens., Paul Casaz, Phillip W. Rice, Charles N. Cole, Ulla Hansen

Dartmouth Scholarship

Simian virus 40 (SV40) large tumor antigen (T antigen) stimulates the activity of the SV40 late promoter and a number of cellular and other viral promoters. We have characterized the ability of T antigens with mutations in the DNA-binding domain and within the N-terminal 85 residues to activate the SV40 late promoter. T antigens lacking both nonspecific and sequence-specific DNA-binding activities were able to induce the late promoter. Mutations within the N-terminal 85 residues of T antigen diminished activation by less than twofold. Activation by wild-type and most of the mutant T antigens required intact binding sites for the cellular …

Modulation Of Neutrophil Functions By Neurotransmitters Implicated In Stress, Chok Ping Wan

Loma Linda University Electronic Theses, Dissertations & Projects

Stress has long been implicated in immune modulation. People under chronic stress have no change in the circulating basal levels of catecholamines while plasma levels of neuropeptide Y (NPY) are significantly increased. Sympathetic nerve fibers with NPY have been found to innervate immune organs. It was hypothesized that NPY might be a mediator in immune modulation in people under chronic stress. Human neutrophils were used as a model to study the effects of NPY alone or together with norepinephrine on the immune system. We now report that NPY modulates oxidative burst (OB) triggered by zymosan in human neutrophils while it …

A Model Of Cytomegalovirus Association With The Development Of Heart Graft Atherosclerosis, Evan Skowronski

Loma Linda University Electronic Theses, Dissertations & Projects

The development of graft atherosclerosis in heart transplant recipients has been associated with the development of post-transplant cytomegalovirus infection. The mechanism of this involvement, however, remains unclear. I undertook a study to determine the role of cytomegalovirus in the development of graft atherosclerosis. First, a rapid method of detecting cytomegalovirus based on capillary polymerase chain reaction and gel electrophoresis was employed to determine the presence of cytomegalovirus in a wide variety of clinical samples. Detection of cytomegalovirus is a lengthy procedure under normal conditions, and timely detection of cytomegalovirus in transplant recipients may allow intervention early enough to block the …

Increased Abundance Of The Receptor-Type Protein-Tyrosine Phosphatase Lar Accounts For The Elevated Insulin Receptor Dephosphorylating Activity In Adipose Tissue Of Obese Human Subjects, Falyaz Ahmad, Robert V. Considine, Barry J. Goldstein

Department of Medicine Faculty Papers

Protein-tyrosine phosphatases (PTPases) have an essential role in the regulation of the steady-state phosphorylation of the insulin receptor and other proteins in the insulin signalling pathway. To examine whether increased PTPase activity is associated with adipose tissue insulin resistance in human obesity we measured PTPase enzyme activity towards the insulin receptor in homogenates of subcutaneous adipose tissue from a series of six lean and six nondiabetic, obese (body mass index > 30) subjects. The obese subjects had a mean 1.74-fold increase in PTPase activity (P < 0.0001) with a striking positive correlation by linear regression analysis between PTPase activity and body mass index among all of the samples (R = 0.918; P < 0.0001). The abundance of three candidate insulin receptor PTPases in adipose tissue was also estimated by immunoblot analysis. The most prominent increase was a 2.03-fold rise in the transmembrane PTPase LAR (P < 0.001). Of the three PTPase examined, only immunodepletion of LAR protein from the homogenates with neutralizing antibodies resulted in normalization of the PTPase activity towards the insulin receptor, demonstrating that the increase in LAR was responsible for the enhanced PTPase activity in the adipose tissue from obese subjects. These studies suggest that increased PTPase activity towards the insulin receptor is a pathogenetic factor in the insulin resistance of adipose tissue in human obesity and provide evidence for a potential role of the LAR PTPase in the regulation of insulin signalling in disease states.

Heterozygosity Mapping Of Partially Congenic Lines: Mapping Of A Semidominant Neurological Mutation, Wheels ( Whl), On Mouse Chromosome 4, Patrick M. Nolan, Patricia J. Sollars, Barbara A. Bohne, Warren J. Ewens, Gary E. Pickard, Maja Bucan

School of Veterinary and Biomedical Sciences: Faculty Publications

We identified a semidominant, chemically induced, mouse use mutation with a complex array of abnormal behaviors including bidirectional circling and hyperactivity, abnormal circadian rhythmicity and abnormal responses to light. In this report, we genetically and phenotypically characterized the circling/ waltzing component of the abnormal behavior. We mapped the locus controlling this trait by heterozygosity mapping of partially congenic lines carrying the mutagenized chromosome outcrossed to different inbred strains for three generations. Analysis of 68 PCR-based markers in 13 affected individuals indicated that the mutant locus, named Wheels (Whl), resides in the subcentromeric portion of mouse chromosome 4. The …